rs104886161

Variant names:

• chrX-108601989-G-A
• rs104886161
• NM_033380.3:c.2146G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108601989-G-A
• chrX-108601989-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_033380.3(COL4A5):​c.2146G>A​(p.Gly716Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/27 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G716G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.07
• Publications: 0 publications found

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-108601989-G-A is Pathogenic according to our data. Variant chrX-108601989-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1077046.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2146G>A	p.Gly716Ser	missense_variant, splice_region_variant	Exon 27 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2146G>A	p.Gly716Ser	missense_variant, splice_region_variant	Exon 27 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.970G>A	p.Gly324Ser	missense_variant, splice_region_variant	Exon 11 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2146G>A	p.Gly716Ser	missense_variant, splice_region_variant	Exon 27 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 917930 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 245198

African (AFR) AF: 0.00 AC: 0 AN: 22897

American (AMR) AF: 0.00 AC: 0 AN: 29832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17738

East Asian (EAS) AF: 0.00 AC: 0 AN: 28055

South Asian (SAS) AF: 0.00 AC: 0 AN: 47430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38167

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 690189

Other (OTH) AF: 0.00 AC: 0 AN: 39888

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1

-

Precision Medicine Center, Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1:Null variant in the gene with established LOF as a disease mechanism PM2:not found in gnomAD PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;.
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;D;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0070	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.85
MutPred		0.98		Gain of phosphorylation at G716 (P = 0.0062);Gain of phosphorylation at G716 (P = 0.0062);.;
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: -42
DS_DL_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104886161; hg19: chrX-107845219;